Statistical Analysis Plan and Clinical Study Report

1
Statistical Analysis Plan and Clinical Study
Report

• Zibao Zhang (???), PhD
• Associate Director, Biostatistics
• PPD China
• Presented at the 2nd Clinical Data Management
  Training
• September 2010, SMMU, Shanghai

2
Before Presentation

• This slide deck is based on Jain Chungs
  presentation for the 1st CDM training course in
  2008.

3
DM Flow
Data Key In
Yes
No
Any Query?
QA staff Quality Control
DM send Query Report
Database Quality Control Report
Site Respond Queries
Update Database
Study Start Up
Conduct
Close out
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Outline

• Introduction of Statistical Analysis Plan
• Introduction of CSR contents
• Final TLFs and Review CSR

5
ICH E9 Statistical Principles
6
ICH E3 Clinical Study Reports
7
Introduction of Statistical Analysis Plan (SAP)

• What is SAP?
• Why need a SAP?
• When write a SAP?
• What are included in the content?
• Who write the SAP?

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Statistical Analysis Plan is ... (ICH E9)

• a document that contains a more technical and
  detailed elaboration of the principal features of
  the analysis described in the protocol, and
  includes detailed procedures for executing the
  statistical analysis of the primary and secondary
  variables and other data.

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What is SAP?

• Also called Data Analysis Plan (DAP)
• An essential document for biometrics activities
• A guidance for a final clinical study report
• A guidance for analysis program development

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Why Need a SAP?

• Provide details of data handling rules and
  statistical analysis methods used for efficacy
  and safety reporting
• Identify all tables, listings, and figures to be
  used for the reports
• Document detail deviations from the protocol
• Facilitate SAS program development
• Fulfill Health Authority requirements

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When write a SAP?
Study Timeline
FPI
LPI
DB Lock
CSR
LPLO
IA
Study Setup
Study Conduct
Data clean
Final Analysis
Interim Analysis
Finalized Protocol
SAP
Pre-lock Analysis
Final SAP
Annotated CRF
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What Are Included in the Content?

1. General information
2. Evaluations Perform. Before DB closure
3. Analysis Populations
4. Patient Disposition
5. Baseline Characteristics

• Efficacy Analysis
• PK/PD Analysis (if applicable)
• Safety Analysis
• References
• Appendices

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1. General Information

• Protocol number
• Title
• Study Objectives
• Study design
• Sample size and randomization algorithm

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2. Evaluations Performed Analysis before
Database Closure

• Evaluation of possibility of introduction of
  biases
• DSMB activities
• Interim analysis
• Procedures used for program development and
  validation
• Exact procedure for handling blinding
• Early/late pre-analysis reviews of blinded data

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2.2 DSMB

• Composition, purpose and responsibility
• Membership (internal, external or mixed)
• Project team members involved
• Performed by third party outside Biometrics
  Reporting objects should not be described in SAP
  but in DSMB Charter

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2.3 Interim Analysis

• Interim analysis performed by Biometrics have to
  be included the followings in the SAP
• The purpose
• Timing of analysis
• Un-blinding procedure/integrity
• Individual patient results or patient summaries,
  display of treatment arms (yes/no)
• Distribution of results

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3. Analysis Populations

• Definition of patient populations including
  details of the criteria used for classification
• ITT (FAS)
• PP
• Safety
• Others

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4. Patient Disposition

• Counting the number of patients
• Included in the study
• Randomized
• Treated
• In ITT and PP
• In Safety Analysis
• Prematurely withdrawn

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5. Baseline Characteristics

• Assess the comparability among treatment groups
• Demographics
• Baseline characteristics
• Previous disease/medications
• Concomitant medication/procedures

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6. Efficacy Analysis

• Sufficient level of details to enable a third
  party to repeat the analysis
• Definition of time windows
• Definition of baseline values
• Descriptions of derivation algorithms
• Definitions of primary, secondary, tertiary
  endpoints
• Statistical methods and models used
• Detail information of handling multiplicity and
  missing data
• Sensitivity analysis (e.g. different data
  handling rules)
• Robustness analysis (e.g. different analysis
  populations)
• Subgroup analyses
• Additional Exploratory Analysis

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7. PK/PD Analysis if applicable

• PK/PD analysis datasets
• The data presentations for the PK profiles and
  derived PK parameters that produced for the CSR
• This should be done in collaboration with
  Clinical
• Pharmacologist
• Modeling, derivation and simulation performed by
  Clinical Pharmacologist if applicable

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8. Safety Analysis

• Exposure to study medication
• Adverse Events (specifies special adverse events)
• AE by body system and preferred terms
• Serious AEs
• AE by intensity and by relationship
• Withdrawals
• Death
• Laboratory Parameters
• Special Areas of Interest (anything additional)
• Vital Signs
• ECGs

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May also be Included in SAP

• Immunogenicity analyses (if applicable)
• Follow up analysis
• Changes from protocol DAS and additions after
  Database closure
• Separate (sub-)sections for statistical methods,
  multiplicity adjustments, ground rules and data
  Handling conventions

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References

• List all references used in the SAP

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Appendices

• List of appendices attached to the SAP
• Appendices may include an example of a
  questionnaire, an example of statistical output,
  study flow chart, key derivation or definitions,
  list of TLFs, etc.

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Who write the SAP?

• Study Statistician

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Introduction of CSR Contents
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Process for Development Clinical Study Report
PGM
ST
Finalized Protocol
SAP TLFs
SAP
Program Development
SAP(A)
Program Validation
Prelock Run(s)
SAP(B)
CS
Database Lock
DM
Review SAP
Stat Outputs Available
Outputs Review
ST PGM
Finalize CSR Structure and identify tables
required
Starting CSR Section 1 2
CSR DRAFT
Starting Section 3,4,5
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Sample of CSR Report BodyIn the format of the
Journal-Style scientific paper

• Background, Rationale and Objectives
• Materials And Methods
• Results
• 3.1 Study Population
• 3.2 Efficacy Results
• 3.3 Pharmacodynamic, Pharmacokinetic and
  PK/PD Modeling
• 3.4 Safety Analysis
• 4. Discussion
• 5. Conclusion
• 6. References
• Appendices

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Sample of CSR Report Body In the format of ICH
E3 Structure and Content of Clinical Study
Reports

• 1. Title page
• 2. Synopsis
• 3. Table of contents
• 4. List of abbreviations
• 5. Ethics
• 6. Investigators and study administrative
  structure
• 7. Introduction
• 8. Study objectives
• 9. Investigational plan

• 10. Study patients
• 11. Efficacy evaluation
• 12. Safety evaluation
• 13. Discussion and overall conclusions
• 14. Tables, figures and graphs referred to but
  not included in the text
• 15. Reference list
• 16. Appendices

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CSR Section 3 - Results

• 3.1 Study Population
• 3.1.1 Disposition of Patients
• 3.1.2 Patients Withdrawn Prematurely
  from treatment
• 3.1.3 Overall of Analysis Populations
• 3.1.4 Protocol Violations
• 3.15 Demographic Data and Baseline
  Characteristics
• 3.1.6 Previous Concomitant Medications
  and Diseases

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CSR Section 3 - Results

• 3.2 Efficacy Results
• 3.2.1 Primary Efficacy Parameter
• 3.2.2 Secondary Efficacy Parameter (s)
• 3.1.3 Subgroup and Exploratory Analyses
• 3.3 Pharmacodynamic, Pharmacokinetic and PK/PD
  Modeling

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CSR Section 3- Results

• 3.4 Safety Analysis
• 3.4.1 Extent of Exposure to Trial
  Medication
• 3.4.2 Overview of Safety
• 3.4.3 Adverse Events
• 3.4.3.1 Overview Adverse Events
• 3.4.3.2 Deaths
• 3.4.3.3 Serious Adverse Events
• 3.4.3.4 Adverse Events and Laboratory
  abnormalities Leading to Withdrawal from
  treatment
• 3.4.3.5 Dose Modifications for Safety
  Reasons

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CSR Section 3 - Results

• 3.4.4 Laboratory Parameters
• 3.4.4.1 Mean (or Median) Change from
  Baseline
• 3.4.4.2 Shift from Baseline
• 3.4.5 Vital Signs
• 3.4.6 ECGs

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Other CSR Sections 4, 5, and 6

• 4. Discussion
• 5. Conclusion
• 6. References
• Appendices

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Review CSR, final TLFs

• Validation
• Consistency
• Interpretations
• Discussions

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BACK-UP SLIDES
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CSR Section 1 Background, Rationale and
Objectives

• 1.1 Background
• 1.2 Rationale
• 1.3 Objective

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CSR Section 2 - Materials and Methods

• 2.3 Compliance with Good Clinical Practice
• 2.3.1 Ethics
• 2.3.2 Audits
• 2.3.3 Data Quality Assurance
• 2.4 Trial Medication
• 2.4.1 Rationale for Dosage Selection
• 2.4.2 Formulation and Packaging
• 2.4.3 Assignment to Treatment
  Group/Sequence
• 2.4.4 Blinding
• 2.4.5 Drug Administration
• 2.4.6 Dose Modification
• 2.4.7 Dose Accountability and Compliance

• 2.1 Overall Study Design
• 2.1.1 Protocol Amendments
• 2.2 Study Population
• 2.2.1 Overview
• 2.2.2 Inclusion Criteria
• 2.2.3 Exclusion Criteria
• 2.2.4 Criteria for Withdrawal from
  Treatment or Study and Replacement Policy
• 2.2.5 Concomitant Medication,
  Treatments and Procedures

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ICH E3 Structure and Content of Clinical Study
Reports

• 1. Title page
• 2. Synopsis
• 3. Table of contents
• 4. List of abbreviations
• 5. Ethics
• 6. Investigators and study administrative
  structure
• 7. Introduction
• 8. Study objectives
• 9. Investigational plan

• 10. Study patients
• 11. Efficacy evaluation
• 12. Safety evaluation
• 13. Discussion and overall conclusions
• 14. Tables, figures and graphs referred to but
  not included in the text
• 15. Reference list
• 16. Appendices
• Details for Sections 9 12 on next slides

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ICH E3 Structure and Content of Clinical Study
Reports (cont.)

• 9. Investigational plan
• 9.1 Overall study design and plan description
• 9.2 Discussion of study design, including the
  choice of control groups
• 9.3 Selection of study population
• 9.3.1 Inclusion Criteria
• 9.3.2 Exclusion Criteria
• 9.3.3 Removal of Patients from Therapy or
  Assessment
• 9.4 Treatments
• 9.4.1 Treatments Administered
• 9.4.2 Identity of Investigational Product(s)
• 9.4.3 Method of Assigning Patients to Treatment
  Groups
• 9.4.4 Selection of Doses in the Study

• 9.4 Treatments (cont.)
• 9.4.5 Selection and Timing of Dose for each
  Patient
• 9.4.6 Blinding
• 9.4.7 Prior and Concomitant Therapy
• 9.4.8 Treatment Compliance
• 9.5 Efficacy and safety variables
• 9.5.1 Efficacy and Safety Measurements Assessed
  and Flow Chart
• 9.5.2 Appropriateness of Measurements
• 9.5.3 Primary Efficacy Variable(s)
• 9.5.4 Drug Concentration Measurements
• 9.6 Data quality assurance
• 9.7 Statistical methods planned in the protocol
  determination of sample size
• 9.8 Changes in the conduct of the study or
  planned analyses

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ICH E3 Structure and Content of Clinical Study
Reports (cont.)

• 10 Study patients
• 10.1 Disposition of patients
• 10.2 Protocol deviations
• 11. Efficacy evaluation
• 11.1 Data sets analyzed
• 11.2 Demographic and other baseline
  characteristics
• 11.3 Measurements of treatment compliance
• 11.4 Efficacy results and tabulations of
  individual patient data

• 12. Safety evaluation
• 12.1 Extent of exposure
• 12.2 Adverse events (AEs)
• 12.3 Deaths, other SAEs, and other significant
  adverse events
• 12.4 Clinical laboratory evaluation
• 12.5 Vital signs, physical findings and other
  observations related to safety
• 12.6 Safety conclusions

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References

• ICH Guidelines www.ich.org
• E9 Statistical Principles for Clinical Trials
• E3 Structure and Content of Clinical Study
  Reports

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Contact

• Zibao Zhang, PhD
• AD BIOSTATISTICS
• PPD China
• T 86 (21) 5383 4000 ext. 606
• C 86 139 1854 6055
• E zibao.zhang_at_excel-cro.com
• Addr Suite 1709, Liu Lin Tower
• No.1 Huai Hai Zhong Lu, Shanghai